1-206772393-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000572.3(IL10):c.43G>A(p.Gly15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,614,206 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

IL10
NM_000572.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.178

Publications

14 publications found

Variant links:

COSMIC-nc: COSV65594408

Genes affected

IL10 (HGNC:5962): (interleukin 10) The protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. Mutations in this gene are associated with an increased susceptibility to HIV-1 infection and rheumatoid arthritis. [provided by RefSeq, May 2020]

IL10 links:

IL19 (HGNC:5990): (interleukin 19) The protein encoded by this gene is a cytokine that belongs to the IL10 cytokine subfamily. This cytokine is found to be preferentially expressed in monocytes. It can bind the IL20 receptor complex and lead to the activation of the signal transducer and activator of transcription 3 (STAT3). A similar cytokine in mouse is reported to up-regulate the expression of IL6 and TNF-alpha and induce apoptosis, which suggests a role of this cytokine in inflammatory responses. Alternatively spliced transcript variants encoding the distinct isoforms have been described. [provided by RefSeq, Jul 2008]

IL19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010133684).

BP6

Variant 1-206772393-C-T is Benign according to our data. Variant chr1-206772393-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456662.

BS2

High Homozygotes in GnomAdExome4 at 11 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IL10	NM_000572.3 link	c.43G>A	p.Gly15Arg	missense_variant	Exon 1 of 5	ENST00000423557.1	NP_000563.1
IL19	NM_153758.5 link	c.-149+1315C>T		intron_variant	Intron 1 of 6	ENST00000659997.3	NP_715639.2
IL10	NR_168466.1 link	n.102G>A		non_coding_transcript_exon_variant	Exon 1 of 6
IL19	NM_001393490.1 link	c.-149+1563C>T		intron_variant	Intron 1 of 6		NP_001380419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL10	ENST00000423557.1 link	c.43G>A	p.Gly15Arg	missense_variant	Exon 1 of 5	1	NM_000572.3	ENSP00000412237.1
IL19	ENST00000659997.3 link	c.-149+1315C>T		intron_variant	Intron 1 of 6		NM_153758.5	ENSP00000499459.2

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

265

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00188

AC:

473

AN:

251274

AF XY:

0.00192

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00344

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00319

AC:

4662

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2258

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000475

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00110

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00395

AC:

4393

AN:

1111996

Other (OTH)

AF:

0.00187

AC:

113

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

253

507

760

1014

1267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00174

AC:

265

AN:

152348

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

127

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41574

American (AMR)

AF:

0.00150

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00313

AC:

213

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.00193

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00189

AC:

229

EpiCase

AF:

0.00267

EpiControl

AF:

0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IL10: BP4 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS4, BP4, PS3_supporting -

Rheumatoid arthritis;C1836230:Susceptibility to HIV infection;C3280677:Graft-versus-host disease, susceptibility to

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IL10 NM_000572.2 exon 1 p.Gly15Arg (c.43G>A): This variant has been reported in the literature in at least 2 individuals with inflammatory bowel disease (IBD), segregating with disease in 1 affected family member (van der Linde 2003 PMID:12825869, Christodolou 2013 PMID:22543157). However, this variant is present in 0.3% (430/126546) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-206945738-C-T). This variant is present in ClinVar (Variation ID:456662). This variant amino acid Arginine (Arg) is present in 3 mammals (Dolphin, Killer Whale, Megabat); this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In addition, in vitro functional studies also suggest that this variant will impact the protein (van der Linde 2003 PMID:12825869). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inflammatory bowel disease

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.73

M_CAP

Benign

0.046

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.3

PhyloP100

0.18

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.34

Sift4G

Benign

0.31

Polyphen

0.023

Vest4

0.40

MutPred

0.79

Gain of methylation at G15 (P = 0.0122);

MVP

0.75

MPC

0.29

ClinPred

0.0095

GERP RS

1.7

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.093

gMVP

0.52

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over